Molecular characterization of Skap2 for integrin activation and leukocyte activation and recruitment
Final Report Abstract
Integrin activation is required for neutrophil functions. Impaired integrin activation on neutrophils is the hallmark of leukocyte adhesion deficiency (LAD) syndrome in humans, characterized by impaired leukocyte recruitment and recurrent infections. In mice, loss of Src kinase-associated phosphoprotein 2 (Skap2) is sufficient to cause a LAD-like phenotype in mice. In this study we demonstrate that Skap2 plays a pivotal role during integrin activation and neutrophil recruitment. Reduced leukocyte recruitment in a model of sterile liver injury, and also acute kidney injury, improved outcome and ameliorated disease severity in Skap2- deficient mice compared to WT mice. We analyzed in detail the function of Skap2 and provide evidence, that Skap2-function is dependent on the direct interaction with Wiskott-Aldrich syndrome protein (WASp) via it SH3 domain. Furthermore, Skap2 regulates integrin-mediated outside-in signaling events and neutrophil effector functions, such as release of reactive oxygen species, phagocytosis, or the release of neutrophil extracellular traps. Due to this central role during inflammation, it might be a promising target for potential therapeutic interventions during sterile inflammatory disorders.
Publications
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Skap2 is required for β2 integrin-mediated neutrophil recruitment and functions. J Exp Med. 2017 Mar 6;214(3):851-874
Boras, Mark; Volmering, Stephanie; Bokemeyer, Arne; Rossaint, Jan; Block, Helena; Bardel, Bernadette; Van Marck, Veerle; Heitplatz, Barbara; Kliche, Stefanie; Reinhold, Annegret; Lowell, Clifford & Zarbock, Alexander
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The integrin-linked kinase is required for chemokinetriggered high-affinity conformation of the neutrophil β2-integrin LFA-1. Blood. 2020 Nov 5;136(19):2200-2205
Margraf, Andreas; Germena, Giulia; Drexler, Hannes C. A.; Rossaint, Jan; Ludwig, Nadine; Prystaj, Barbara; Mersmann, Sina; Thomas, Katharina; Block, Helena; Gottschlich, Wiebke; Liu, Chang; Krenn, Peter W.; Haller, Hermann; Heitplatz, Barbara; Meyer zu Brickwedde, Marika; Moser, Markus; Vestweber, Dietmar & Zarbock, Alexander
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Diabetes With Multiple Autoimmune and Inflammatory Conditions Linked to an Activating SKAP2 Mutation. Diabetes Care. 2021 Aug;44(8):1816-1825
Rutsch, Niklas; Chamberlain, Chester E.; Dixon, Wesley; Spector, Lauren; Letourneau-Freiberg, Lisa R.; Lwin, Wint W.; Philipson, Louis H.; Zarbock, Alexander; Saintus, Karline; Wang, Juehu; German, Michael S.; Anderson, Mark S. & Lowell, Clifford A.
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SKAP2 as a new regulator of oligodendroglial migration and myelin sheath formation. Glia. 2021 Nov;69(11):2699-2716
Ghelman, Julia; Grewing, Laureen; Windener, Farina; Albrecht, Stefanie; Zarbock, Alexander & Kuhlmann, Tanja
